plants Review Tragia L. Genus: Ethnopharmacological Use, Phytochemical Composition and Biological Activity Rodrigo Duarte-Casar 1,2 and Juan Carlos Romero-Benavides 2, * 1 2 *



 Maestría en Química Aplicada, Facultad de Ciencias Exactas y Naturales, Universidad Técnica Particular de Loja, Loja 110108, Ecuador; rduarte@utpl.edu.ec Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Técnica Particular de Loja, Loja 110108, Ecuador Correspondence: jcromerob@utpl.edu.ec; Tel.: +593-98-770-8487 Abstract: Tragia L. is a genus of plants belonging to the Euphorbiaceae family with worldwide intertropical distribution, composed of more than 150 species. In this literature review, 26 species of the genus used as medicinal plants were found, mainly in East Africa and the Indian subcontinent, with a variety of uses among which antibacterial, anti-inflammatory, anticancer and reproductive health are most common. Research has been done on a few of the species, mostly those of the Old World, with emphasis on four of them: Tragia involucrata Linn., Tragia spathulata Benth., Tragia benthamii Baker and Tragia plukenetii Radcl.-Sm., confirming several ethnomedicinal claims. Moreover, a variety of active phytochemicals have been isolated, mainly ethers, hydrocarbons, flavonoids and sterols. There is ample field for the evaluation of the activity of Tragia extracts and essential oils and the identification of their active compounds, particularly of the New World species, for which there is still very little research. Citation: Duarte-Casar, R.; Romero-Benavides, J.C. Tragia L. Keywords: Tragia; ethnopharmacology; phytochemicals; Euphorbiaceae; biological activities Genus: Ethnopharmacological Use, Phytochemical Composition and Biological Activity. Plants 2021, 10, 2717. https://doi.org/10.3390/ 1. Introduction plants10122717 Plants have been used as a source of medicinal substances for a long time, with a use that amply predates history and presumably even mankind [1–3], and the discovery of active species and their use has historically been characterized by a trial-and-error approach [4]. This empirical knowledge has been and is being alidated by systematic research and is used as a guideline to direct the search for better and new drugs, integrating ancestral knowledge and modern methods [5]. Among the plant families considered medicinal, Euphorbiaceae is well regarded. The ample geographical distribution of the family and the variety of stress conditions the plants grow in, which trigger the production of secondary metabolites [6], partially explain the abundance and variety of biologically active compounds found in the family and thus its medicinal activity [7,8]. This review endeavors to summarize the current knowledge about species of the Tragia genus, which belongs to the Euphorbiaceae family, concerning their medicinal properties, phytochemical basis, and in vitro and in vivo evidence and envisioning future research prospects. Academic Editor: Antonella Smeriglio Received: 24 September 2021 Accepted: 7 December 2021 Published: 10 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 2. Genus The genus Tragia is one of the 317 genera in the Euphorbiaceae family. There are 161 accepted names belonging to 154 species in the Tragia genus, with “pantropical and warm temperate distribution” [9,10]. The etymology for the name of this genus comes from the Greek tragos, meaning goat. This name may stem either from the name of the German botanist Hieronymus Bock—Bock means “ram” or “he-goat” in German, or from the hairy appearance of the plant that would resemble a male goat [11]. Plants 2021, 10, 2717. https://doi.org/10.3390/plants10122717 https://www.mdpi.com/journal/plants Plants 2021, 10, 2717 2 of 20 Tragia species exhibit very ample morphological characters: they are perennial plants with herb, shrub, subshrub and twining vine growth habits, with lanceolate leaves presenting either entire or serrated margins. Plants belonging to this genus sting when touched due to the presence of leaf hairs with a needle-shaped crystal of calcium oxalate (raphide) in the terminal cells that is expelled on contact and punctures the skin, allowing irritants to enter and cause transient stinging [12,13], presumably a defense mechanism against herbivores [14]. Several common names for Tragias, such as noseburn (Tragia spp.), Indian stinging nettle (T. involucrata), fireman (T. volubilis) or stinging nettle creeper (T. durbanensis), are due to this stinging property. Figure 1 shows T. involucrata leaf hairs with raphides visible, taken in Kerala, India, and T. ramosa with clearly visible raphides, taken in Nevada, USA. Figure 1. Tragia involucrata leaves, left. Tragia ramosa showing leaf and stem, covered by long, rough Scheme 3.0 license; right, Stan Shebs, GDFL license. Species belonging to Euphorbiaceae in general and to Tragia in particular are still not fully settled [8], as new species are being discovered [15] and species are being reassigned to other genera [9,16], so the number of species in the genus is still subject to change. 3. Distribution and Localization Species belonging to the Tragia genus are present in subtropical America, Eastern and Southern Africa, the Indian subcontinent and Northeastern Australia. Of the 154 species listed in the genus [17], 94 are found in Africa, 48 in America, 10 in Asia and 3 in Oceania, with some species such as T. arabica and T. plukenetii present both in Africa and Asia. The map in Figure 2 shows the intertropical distribution of Tragia species by country. Figure 2. Worldwide Tragia species distribution, by country. Plants 2021, 10, 2717 3 of 20 4. Methodology Published works (articles and patents) were searched on scientific databases—Science Direct, Google Scholar and Scopus—for each species of the genus, using inverted commas for an exact match, e.g., “Tragia acalyphoides”. Relevant articles were selected after removing search terms unrelated to the area of interest such as corrosion, reforestation or hare diet. When abundant results were obtained, the search was refined with more specific terms, for example “Tragia involucrata medicinal” or “Tragia involucrata ethnopharmacology”. Duplicate articles were removed, and the remaining articles were reviewed with a focus on ethnopharmacological uses, phytochemical composition and biological activity, both in vitro and in vivo. When possible, the latest articles, no older than 10 years, have been cited. Preprints were not included. The research interest in Tragia species in medical and health sciences has increased during the last twenty years. Figure 3 shows the number of publications that include the word Tragia in their text in the fields mentioned. Even though the subject is not a very popular one, a steady increase in appearances can be seen, with a marked increase between 2019 and 2020 and the first half of 2021. Figure 3. Publications containing the word Tragia since the year 2000 in Medical and Health sciences and in Chemical sciences. Data source: [18]. Compared to the other genera in the Plukenieteae tribe, Tragia concentrates 67% of the research, compared to 12% for Cnesmone, 10% for Acidoton, 4% for Sphaerostylis and 1% each for Megistostigma, Pachystylidium, Platygyna and Tragiella [18]. 5. Ethnopharmacological Usage Of the more than 150 species of the genus, few appear in the scientific literature, and even fewer are mentioned from an ethnopharmacological perspective. Notwithstanding, Tragia species are a part of traditional medicinal systems of East Africa and the Indian subcontinent, such as Siddha and Ayurveda [19], with documented uses of T. involucrata appearing as early as the 1st century CE [20] and with only a handful of mentions of Tragia species in the New World pharmacopoeia, concerning mostly topical applications. There is concern over an excessive use of Tragia species, e.g., Tragia bicolor, which poses a conservation hazard [21,22]. Plants 2021, 10, 2717 4 of 20 Most of the interest in this genus has been focused on four species: Tragia involucrata, Tragia spathulata, Tragia plukenetii and Tragia benthamii [23], with the bulk of the research focused on T. involucrata. Nevertheless, several more species and their medicinal uses appear in literature. Table 1 summarizes the species with reported medicinal use along with their stated ethnopharmacological uses, when available. The Anatomical Therapeutic Chemical (ATC) Classification by the World Health Organization (WHO) is used to classify the uses for each species [24]. Figure 4 shows the geographical distribution of the documented uses. The ethnomedical uses of Tragia spp are most abundant in the Indian subcontinent and East and Southern Africa. Table 1. Tragia species and their ethnopharmacological use. Species are listed in alphabetical order and validated against [25]. Species Region Plant Organs Used Use Form of Usage ATC Category References Tragia aliena Pax and K.Hoffm. Brazil NS Medicinal (not specified) NS V [26] Tragia benthamii Baker Nigeria, Cameroon Whole plant Leaves, roots Whole plant Abortifacient Antimalarial Filaricidal Decoction NS G P P [27] [28] [23] Tragia bicolor Miq. India, Sri Lanka NS Medicinal NS V Tragia brevipes Pax. Rwanda, Kenya Leaves Anticancer Antigonorrhoeic Aphrodisiac Erectile dysfunction Obesity Uterotonic Decoction Chewing Ash L G G G A G [21] [29] [30] [31] [32] [33] [34] [35] [36] Tragia cinerea (Pax) M.G.Gilbert and Radcl.-Sm. Ethiopia Leaves NS Antigonorrhoeic Anti-inflammatory Aphrodisiac Powdered plant, drunk mixed with butter/honey G M G [37] [38] Tragia cordata Michx. America, Ethiopia Roots Urinary tract and external parasites Decoction Topical (powdered root) G D [39] Tragia dioica Sond. South Africa Leaves Fatigue Tuberculosis NS V J [40] Tragia doryodes M.G. Gilbert Ethiopia Leaves Anthrax Decoction J [41] Tragia durbanensis Kuntze. South Africa NS Skin rashes NS D [42] Roots Abscess Analgesic Antimalarial Aphrodisiac Paralysis Cold water maceration, drunk J N P G N [43] [44] [45] Emollient Rubefacient Diuretic Antirheumatic NS D D G M [46] [47] Tragia furialis Bojer Tanzania, Madagascar Tragia geraniifolia Klotzsch ex Müll.Arg. Argentina Tragia gracilis Griseb. Cuba NS Not specified NS V [48] Tragia hildebrandtii Müll.Arg. India NS Not specified NS V [49] Tragia hispida Willd. Sri Lanka NS Tooth decay NS A [50] Tragia insuavis Prain. Kenya Endophytes Antibacterial NS J [51] Southern Asia (India, Sri Lanka, Bangladesh) Whole plant, Leaves, Roots Analgesic Antidiabetic Anti-inflammatory Antimicrobial Antinociceptive Antioxidant Antiparasitic Antitumor Diuretic Hepatoprotective Decoction Juice Poultice N A M J N – D L G N [20,52] [53] [23] [54] [55] [56] [57] [58] South Africa NS Leaves, Stems NS (barks, stems and corms mentioned) Aphrodisiac Antineoplastic Immune booster Decoction G L L [59] [60] [61] Tragia involucrata L. Tragia meyeriana Müll.Arg. Roots NS Plants 2021, 10, 2717 5 of 20 Table 1. Cont. Species Region Plant Organs Used Use Form of Usage ATC Category References Tragia mitis Hochst. ex A.Rich. Ethiopia Root Antidiarrheal Crushed, mixed with water and sugar A [62] Tragia mixta M.G.Gilbert Djibouti Leaves Analgesic Stomach aches Tonsilitis Heated Poultice N A A [63] [64] Powdered, drunk with water N V B G [65] [66] Tragia okanyua Pax Namibia NS Root Dizziness Snake bite Cardiovascular problems Sexually transmitted diseases (STD) Tragia plukenetii Radcl.-Sm. East Africa, India Leaves Antihyperglycemic Antitumor Decoction A L [23] Tragia praetervisa Chakrab. & N.P.Balakr. India, Sri Lanka NS Not specified NS V [49] Tragia preussii Pax Central African Republic Leaves Rheumatism NS M [67] Paste D M L G [68] [69] [70] NS V [71] [72] [73] Tragia pungens (Forssk.) Müll.Arg. Yemen Whole plant Allergy and skin diseases Antirheumatic Cytotoxic Anti-impotence Tragia ramosa Torr. U.S.A., Mexico Leaves Not specified Tragia rupestris Sond. South Africa Whole plant Medicine (not specified) NS V V Tragia senegalensis Müll. Arg Benin Leaves Azoospermia NS G [74] Tragia sonderi Prain Swaziland Root HIV/AIDS Decoction Topical L [75] Tragia spathulata Benth. West Africa Leaves Antibacterial NS J [23] [76] Tragia subsessilis Pax Uganda Root Tuberculosis NS J [77] NS V V [78] Tragia uberabana Müll. Arg Brazil NS Medicinal Toxic Tragia vogelii Keay Burkina Faso Whole plant Abortifacient Decoction G [79] Decoction G V G [80] [26] [46,81] Topical D M [82] Tragia volubilis L. Mexico, Antilles, Brazil Leaves, Stem, Root Diuretic Medicinal STDs Tragia yucatanensis Millsp. Belize, Guatemala, Mexico Leaves Burns Rheumatism NS: not specified. ATC categories are as follows. A: alimentary tract and metabolism, B: blood and blood-forming organs, C: cardiovascular system, D: dermatological, G: genitourinary system and sex hormones, H: systemic hormonal preparations, excluding sex hormones and insulins, J: anti-infective for systemic use, L: antineoplastic and immunomodulating agents, M: musculo-skeletal system, N: nervous system, P: antiparasitic products, insecticides and repellents; R: respiratory system, S: sensory organs; V: various [24], not present in the classification. STDs: sexually transmitted diseases. According to the ATC classification, the most frequent ethnopharmacological uses of Tragia spp. in ethnopharmacology are: genitourinary system and sex hormones, with 19% of occurrences (15 of 77); nervous system, with 12%; and alimentary tract and metabolism, anti-infective for systemic use and antineoplastic and immunomodulating agents with 10% of occurrences each. The “various” classification presents 17% of occurrences, which include non-specified and vague uses, such as “toxic” or “medicinal”. As for the morphological structures used per species, the most common are the leaves, 38%; followed by “not specified”, 33%; whole plant, 15%; roots, 13% and a single occurrence of endophytes (3%). Plants 2021, 10, 2717 6 of 20 Figure 4. Ethnomedicinal uses for Tragia spp. The circle diameter is proportional to the uses reported for each country. 6. Biological Activity Biological activity tests of Tragia, both in vitro and in vivo, are performed mostly with plant extracts and to a much lesser degree with essential oils: leaf, root or the whole plant, although ethnopharmacological uses mostly employ the plant via infusions, decoctions or ashes [23,35]. Different solvents and solvent mixtures have been used for the extracts, mainly methanol and ethanol. Due to the presence of Tragia in ethnomedical traditions in Africa and Asia, there is a team of research about the bioactivity of Old World Tragia extracts that have confirmed their activity and potency in some cases. Not all the health claims or traditional uses recorded have been validated through research. Again, the bulk of the research is centered on T. involucrata. 6.1. In Vitro Activity Extracts of T. benthamii, T. brevipes, T. involucrata, T. pungens and T. spatulatha have been tested to ascertain their in vitro activity for a variety of uses. The in vitro research is summarized in Figure 5. Figure 5. Summary of in vitro activity of Tragia species. Cases in which the efficacy has been shown in vitro are listed in Table 2. Plants 2021, 10, 2717 7 of 20 Table 2. In vitro activity of Tragia extracts. Species are in alphabetical order. Species T. benthamii Extract Methanol Plant Organs Used Whole plant Biological Activity Biological Model Effect Methodology Reference Antibacterial 28 strains (sensitive and MDR) of Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter aerogenes, Escherichia coli, Providencia stuartii Effective against 11/28 strains (39.3%) 256–1024 µg/mL INT colorimetric assay [83] Inhibition zones (mm) +2 +10 +9 +24 +5 +8 500 mg/mL extract—well diffusion assay [84] T. brevipes Methanol: water 9:1 Leaf Antibacterial Escherichia coli, Salmonella spp., Enterobacter aerogenes, Bacillus cereus, Serratia liquefaciens, Proteus vulgaris T. brevipes Methanol:DCM 1:1 Leaf Antiproliferative DU145 HCC HELA +IC50 : 30 µg/mL - Extract MTT [85] T. involucrata Chloroform Root Antidiabetic Fertile eggs of white leghorn chicken + 0.5, 1 mg/egg. Streptozotocin-induced diabetes [86] 50–250 mg/mL. Disc diffusion [53] Agar disc diffusion [87] Agar disc diffusion [88] T. involucrata T. involucrata T. involucrata Ethyl acetate Methanol Isolated hydrocarbons and ethers Root Leaf - Antibacterial Antifungal Antifungal Antibacterial Staphylococcus aureus Bacillus subtilis Bacillus brevis Staphylococcus epidermidis Escherichia coli Shigella disenteriae Pseudomonas aeruginosa Vibrio cholera Inhibition zones (mm) +18 +14 +5.7 +0.6 +17 +3.7 +9.4 +4.7 Trichophyton rubrum Malassezia furfur +3.7 +13.5 Rhizopus stolonifer, Aspergillus niger, Alternaria solani, Mucor indicus, Chaetomium globosum, Tilletia indica Inhibition zone +16 ± 0.3 mm +15 ± 0.2 mm +15 ± 0.6 mm +10 ± 0.5 mm Burkholderia pseudomallei (TES21), Burkholderia pseudomallei (KHW), Klebsiella pneumoniae (ATCC15380) Klebsiella pneumoniae Pseudomonas aeruginosa (ATCC27853), Vibrio damsela, Salmonella typhi (ATCC51812) Inhibition zone mm +23 +25 +20 +19 +28 Plants 2021, 10, 2717 8 of 20 Table 2. Cont. Species Extract Plant Organs Used Biological Activity Biological Model T. involucrata Methanol Ethyl acetate Chloroform Petroleum ether Leaf Antiproliferative K562 cell lines T. involucrata Water +NP Leaf Antiurolithiatic - +Struvite crystal growth inhibitory effect T. involucrata Methanol Whole plant Radioprotective Cultured human peripheral lymphocytes +Pretreatment (10 µg mL−1 ) T. meyeriana and other plant species Boiling water Whole plant Immunomodulatory Isolated peripheral blood mononuclear cells + Staphylococcus aureus +(8–14 mm) Bacillus subtilis Micrococcus flavus Pseudomonas aeruginosa Candida maltosa FL cells +Cytotoxicity. IC50 : 70 µg/mL Staphylococcus aureus, Proteus mirabilis, Klebsiella pneumoniae, Salmonella typhi, Streptococcus pneumoniae, Escherichia coli, Candida albicans, Aspergillus flavus, Fusarium solani MIC (mg/mL) +21 +21 +25 +25 +25 - T. pungens T. spatulatha Methanol Ethanol Methanol Acetone NS Leaf Antibacterial Cytotoxic Antibacterial Antifungal Effect - Methodology Reference MTT [89] 2% extract; AgNPs (200 µg mL−1 ) [90] CHCl3 AcOEt 60 Co gamma irradiation Comet assay [91] S. aureus stimulation. Inflammatory cytokine secretion in THP-1 monocytes [61] Disk diffusion assay, Neutral red uptake assay [69] Agar well diffusion [76] MDR: multi-drug resistant. NP: nanoparticle. DCM: dichloromethane. NS: not specified; INT: p-Iodonitrotetrazolium chloride; MTT: 3-(4-5-dimethyl-2-thiazoly)-2,5-diphenyltetrazolium bromide; MIC; minimum inhibitory concentration; AcOEt: ethyl acetate; AgNP: silver nanoparticles; + active. - not active. Plants 2021, 10, 2717 9 of 20 In vitro biological activity tests devote the most attention to leaves (36%), with whole plant and root used to a lesser extent, with both 14%. Extraction solvents are methanol (47%), DCM (5%), Ethyl acetate (10%), water (6%), chloroform (5%), petroleum ether (5%), ethanol (5%) and acetone (5%). This solvent usage supports the assumption that most active compounds are moderately polar and are thus extracted with polar solvents. Testing centers on antibacterial (41%) and antifungal (18%) activity of the extracts, with antiproliferative (12%) and antidiabetic, antiurolithiatic, radioprotective, immunomodulatory and cytotoxic effects (6% each) behind. This is a different profile than what was found in the ethnomedicinal claims, which centers on the genitourinary system and sex hormones. This is justified because aphrodisiacs do not have the expected properties [92]. 6.2. In Vivo Activity Besides in vitro activity testing, research has been done in animal models, mostly mice and also chicks, with at least one clinical trial performed in humans. The Tragia extracts evaluated in vivo, summarized in Figure 6 and Table 3, are obtained from four species: T. benthamii, T. furialis, T. involucrata and T. plukenetii. Figure 6. Summary of in vivo activity of Tragia extracts. Table 3. In vivo activity of Tragia extracts. Species Extract Plant Organs Used Animal Model Activity Results Reference [27] T. benthamii Ethanol Whole plant Swiss albino mice Antimalarial −Very poor activity against P. berghei (NK-65) at 50 mg·kg−1 bw. T. benthamii Water NS Chick Anti-inflammatory +Carrageenan-induced foot edema. Maximal inhibition 84.3% at 300 mg/kg bw. [93] T. furialis Ethanol–water NS White albino mice Antimalarial +IC50 : 639.3 mg·kg−1 bw against P. berghei. [43] +100–300 mg/kg bw. Hepatoprotective against CCl4 induced toxicity and antioxidant activity; Attenuation of biomarker alteration (SGOT, SGPT, ALP. TP). [57] +0.1–0.4% w/v Oviposition and phagodeterrence, larvicidal. [94] T. involucrata Root Wistar rats Hepatoprotective T. involucrata Benzene: Ethyl acetate 1:1 Root Culex quinquefasciatus Larvicidal T. involucrata Ethanol Leaf Albino rats (male) Nephroprotective +250 and 500 mg/kg bw. Decrease − in serum urea creatinine in · and acetaminophen-induced toxicity. [95] T. involucrata Hexane Ethyl acetate Aerial parts Swiss albino mice Antitumor +50–150 mg/kg bw. Ehrlich’s Ascites Carcinoma. DD antitumor activity and increased life span for both extracts. [96] T. involucrata Hot water NS Wistar rats (male) Diuretic +1650, 2200 mg/kg bw. Loop diuretic action. − [56] T. involucrata Hot water— freeze dried Whole plant Clinical trial Antidiabetic 240 mL decoction/day. FPG decrease from 164.4 ± 20.4 to 130.9 ± 16.2 mg/dL. [52] Swiss albino mice Analgesic Anxiolytic Sedative +200, 400 mg/kg bw. Acetic acid writhing and formalin-induced paw licking; behavioral tests; pentobarbital-induced sleep time. [97] T. involucrata Methanol Leaf − · Plants 2021, 10, 2717 10 of 20 Table 3. Cont. Species Extract Plant Organs Used Animal Model Activity Results Reference T. involucrata Methanol Leaf Wistar rats Antibacterial +100, 200 mg/kg bw. Wound healing in S. aureus infections. [98] T. involucrata Methanol Leaf Swiss albino mice Antiepileptic +400, 800 mg/kg bw MES, PTZ, PTX induced convulsions DD. [99] T. involucrata Methanol NS Swiss albino mice Radioprotective +100 mg/kg bw. DD survival increase [100] T. involucrata Methanol Root Charles-Foster rats Swiss albino mice Analgesic Anti-inflammatory +Carrageenan paw edema, cotton pellet granulomata, acetic acid writhing. [101] T. involucrata Methanol Root Wistar rats Antibacterial +100, 200 mg/kg bw. Wound healing in S. aureus infections [102] [103] T. involucrata Methanol Root Charles−Foster rats Swiss albino mice CNS depressant +100–300 mg/kg bw. Behavioral pattern, spontaneous motility, pentobarbitone-induced sleep, body temperature, aggressive behavior pattern and conditioned avoidance response (CAR). T. involucrata Methanol Chloroform Whole plant Albino rats Anti-inflammatory +100, 300 mg/kg bw. Both extracts. Carrageenan paw oedema. [54] T. involucrata Methanol Ethyl acetate Whole plant Swiss albino mice Analgesic +500 mg/kg bw. Acetic acid model; tail flick model analgesic activity. [55] T. involucrata Water Leaf Wistar rats Swiss mice (male) Anti-inflammatory +50–400 mg/kg bw in carrageenan-induced hindpaw edema and cotton pellet granuloma models. [104] T. involucrata Water +NP Leaf Wistar rats (male) Antiurolithiatic +200 mg/kg bw. CaOx stone formation inhibition in ethylene glycol-induced urolithiasis. [90] T. plukenetii Ethanol Aerial parts Wistar rats (male) Antihyperglycemic +At an oral dose of 150 and 300 mg/kg bw. Oral glucose tolerance test in alloxan induced diabetic rats. [105] Antipyretic Diuretic Antiasthmatic Analgesic Antispasmodic +100 mg/kg bw. +Antipyretic: Brewer’s yeast-induced hyperpyrexia method. +Diuretic: in vivo Lipschitz test method. +Antiasthmatic: Isolation of guinea pig ileum preparation; histamine-induced bronchoconstruction. +Analgesic: acetic acid writhing response. +Antispasmodic: studies on isolated rabbit jejunum. [106] T. plukenetii Ethanol Whole plant Wistar rats Guinea pigs Rabbits T. plukenetii Ethanol Whole plant Swiss albino mice (male) Antitumor +100–300mg/kg bw. Ehrlich ascites carcinoma survivability. Antioxidant parameters increased DD. [107] T. plukenetii Methanol Benzene Chloroform Leaf Swiss albino mice Anticonvulsant +100 mg/kg bw. Methanol extract against PTZ-induced convulsions. [108] NS: not specified; −: no activity; +: activity present; DD: dose-dependent, bw: body weight; MES: maximal electroshock; PTZ: pentylenetetrazol; PTX: picrotoxin; FPG: fasting plasma glucose; SGOT: serum glutamic oxaloacetic transaminase; SGPT: serum glutamic pyruvic transaminase; ALP: alkaline phosphatase. Most of the research (73%) centers on T. involucrata, with T. plukenetii (18%), T. benthamii (9%) and T. furialis (5%) behind. In vivo assay extracts were obtained from leaves (29%), whole plant (25%), root (21%) and aerial parts (8%). Solvents used are methanol (48%), ethanol (26%) and water (13%), which shows that most active compounds are polar and are thus extracted with polar solvents. For both in vitro and in vivo testing, the most common effect is antibacterial and antimicrobial with 22% of the reviewed studies. This is higher than the 10% reported in the ethnopharmacological uses. Effects having to do with cancer prevention and treatment— antiproliferative, antitumor, cytotoxic immunomodulatory and radioprotective—add up to 17% of the reported effects, which makes it the second most frequent use. Analgesic and anti-inflammatory activity is equally reported in 10% of the tests. Plants 2021, 10, 2717 11 of 20 The findings reported in literature validate several medicinal use cases for Tragia species and dismiss some claims, e.g., T. meyeriana as an antineoplastic [60]. 7. Phytochemical Composition Phytochemical studies allow for the identification, separation and isolation of compounds of interest [109]. Based on phytochemical screenings published in the literature, the main secondary metabolites found in Tragia species extracts are alkaloids, glycosides, flavonoids, and sterols [23,110]. Some compounds found in plants belonging to the Tragia genus, classified according to their chemical nature, are listed in Table 4. Where applicable, the biological activity of the identified compound has been mentioned. Identification of the compounds relies heavily on spectroscopic and spectrometric methods [109], and chromatography retention times and comparison with the literature are also used for tentative identification. Figure 7 shows the structure of some of the compounds identified in Tragia extracts and oils, mentioning their biological activity in bold when reported. As expected in plant extracts, there is a variety of secondary metabolites in the form of terpenoids and flavonoids. Ethers and non-terpenoid hydrocarbons are reported as having antibacterial activity, and they are not in any of the common groups of secondary metabolites. There is more information about the activity of the extracts and essential oils than about the activity of compounds on their own. The recent discovery of anti-inflammatory peptides in Tragia benthamii extracts [93] opens a new area of interest in the research of Tragia species. A strength of the genus is its diversity and its pantropical distribution, which makes it readily available in most tropical countries. A weakness would be that, despite the interest shown concerning T. involucrata and other traditionally medicinal species, there appear to be no drugs derived from plants of these species, remaining in the realm of herbal remedies and plant extracts, entailing less medicinal interest than other genera of the Euphorbiaceae family, notably Euphorbia [8]. This can be attributed to the stage of research, with most work performed in vitro or in vivo and with a single clinical trial [52]. Hopefully the current research will advance into new drugs. Plants 2021, 10, 2717 12 of 20 Table 4. Compounds isolated/identified in Tragia extracts and oils and their biological effect. No. Compound Identified Isolated Methodology Used Species Collection area Ethanol extract GC, MS T. plukenetii NS Plant Organ Used Use Effect Reference Whole plant NS NS [111] Acetal 1,1-diethoxy-2methylpropane 1 X Aldehydes Ethanol extract GC, MS Hydrodistillation GC/GC-MS 2 16-heptadecenal X 3 Hexanal X 4 (E)-4-(1-hydroxypropyl)7,8-dimethyl-9-(prop-1-en1-yl)-[1,3] dioxolo [4,5-g]quinolin-6(5H)-one X X 5 4-oxo-4H-pyran-2,6dicarboxylic acid bis-[6-methyl-heptyl] ester X X 6 Ethyl linoleate X X 7 Ethyl palmitate X X T. plukenetii T. benthamii NS Whole plant NS NS [111] Ibadan, Nigeria Leaves NS NS [112] Alkaloid Acidified ethanol extract GC, MS, LC T. plukenetii NS Whole plant NS NS [111] T. involucrata Salem, India Roots Antidiabetic Blood glucose reduction [86] NS Whole plant NS NS [111] NS Whole plant NS NS [111] MBC 12.25 µg/mL [98,113] MIC 1.25-12.5 µg/mL [53] Esters Ethanol extract IR 1 H, 13 C NMR, MS Ethanol extract GC, MS Ethanol extract GC, MS T. plukenetii T. plukenetii Ether T. involucrata Tamil Nadu, India Leaf Antibacterial Escherichia coli Proteus vulgaris Staphylococcus aureus Odisha, India Root Antibacterial Fungicidal Vinyl hexyl ether X X Aqueous extract GC, MS 9 3-(2,4-dimethoxyphenyl)6,7-dimethoxy-2,3dihydrochromen-4-one X X Ethyl acetate extract FTIR, MS, 1 H NMR T. involucrata 10 Iridin X X Root Toxic [53] Quercetin X X Odisha, India Root Antioxidant [53] 12 Rutin X X T. involucrata T. involucrata T. involucrata Odisha, India 11 Ethyl acetate extract FTIR, MS, 1 H NMR Ethyl acetate extract FTIR, MS, 1 H NMR Ethyl acetate extract FTIR, MS, 1 H NMR Odisha, India Root Antioxidant [53] 2,5-dithia-3,6diazabicyclo[2.2.1]heptane X X 95% aqueous ethanol extraction 1 H, 13 C NMR T. benthamii Ibadan, Nigeria Whole plant NS [114] 8 Flavonoids Heterocycle 13 Plants 2021, 10, 2717 13 of 20 Table 4. Cont. No. Compound Identified Isolated Methodology Used Species Aqueous extract GC, MS Aqueous extract GC, MS T. involucrata T. involucrata Collection area Plant Organ Used Tamil Nadu, India Leaf Tamil Nadu, India Leaf Use Effect Reference Hydrocarbons Antibacterial Proteus vulgaris Antibacterial Staphylococcus aureus Antibacterial Escherichia coli Proteus vulgaris Staphylococcus aureus Antibacterial Proteus vulgaris Staphylococcus aureus 14 2,6-dimethylheptane X X MBC 10 µg/mL [98] 15 2,4-dimethylhexane X X MBC 12.25 µg/mL [98] 16 2-methylnonane X X Aqueous extract GC, MS T. involucrata Tamil Nadu, India Leaf MIC 5.0 µg/mL [98] 17 Shellsol (2-methyldecane) X X Aqueous extract GC, MS T. involucrata Tamil Nadu, India Leaf MBC 25.0 µg/mL [98] 18 3,5-di-tert-butyl-4hydroxyanisole X X 95% aqueous ethanol extraction 1 H, 13 C NMR T. benthamii Ibadan, Nigeria Whole plant Antioxidant 19 5-hydroxy-1methylpiperdin-2-one X X Methanol extract IR, 1 H, 13 C RMN, LC T. involucrata Kerala, India Leaf Antihistamine Muscle relaxant, bronchodilating and anti-allergic effects [115] 20 Erythritol X X T. benthamii Ibadan, Nigeria Whole plant NS NS [114] 21 Glycerol X X T. benthamii Ibadan, Nigeria Whole plant NS NS [114] 10,13-dimethoxy-17-(6methylheptan-2-yl)2,3,4,7,8,9,10,11,12,13,14,15,16,17- X tetradecahydro-1Hcyclopenta[α]phenanthrene. X Ethyl acetate extract FTIR, MS, 1 H NMR T. involucrata Odisha, India Root NS NS [53] Aqueous extract GC, MS Hydrodistillation GC/GC-MS Ethanol extract IR, 1 H RMN, LC Ethanol extract IR, 1 H RMN, LC Hydrodistillation GC/GC-MS T. involucrata T. benthamii Leaf NS NS [98] Ibadan, Nigeria Leaves Anti inflammatory [112] T. ramosa Maharashtra, India Leaves Antibacterial [71] T. ramosa Maharashtra, India Leaves NS NS [71] T. benthamii Ibadan, Nigeria Leaves NS NS [112] [114] Polyols 95% aqueous ethanol extraction 1 H, 13 C NMR 95% aqueous ethanol extraction 1 H, 13 C NMR Terpenoids 22 23 Stigmasterol X 24 Caryophyllene X 25 Citronellal X X 26 Clerodane X X 27 Geranylacetone X Plants 2021, 10, 2717 14 of 20 Table 4. Cont. No. Compound 28 Neophytadiene (2-(4,8,12Trimethyltridecyl) buta-1,3-diene) X X 29 Phytol X X 30 Squalene (all trans) X X 31 α-terpinene Identified Isolated X X Methodology Used Species Collection area Plant Organ Used Use Effect Ethanol extract GC, MS T. plukenetii NS Whole plant NS NS [111] T. benthamii Ibadan, Nigeria Whole plant NS NS [114] T. plukenetii NS Whole plant NS NS [111] NS [71] 95% aqueous ethanol extraction 1 H, 13 C NMR Ethanol extract GC, MS Ethanol extract IR, 1 H RMN, LC T. ramosa Maharashtra, India Leaves Antiinflammatory, Antimicrobial Reference GC: gas chromatography; MS: mass spectrometry; LC: liquid chromatography; IR: infrared spectroscopy; NMR: nuclear magnetic resonance; FTIR: Fourier transform infrared spectroscopy; Q-TOF: quadrupole time of flight mass spectrometry; TLC: thin layer chromatography; NS: not specified. Plants 2021, 10, 2717 15 of 20 Figure 7. Compounds identified in Tragia extracts and oils. 8. Conclusions Species belonging to the Tragia genus are present in traditional medicine in several cultures and have multiple uses, among which antibacterial, anticancer and aphrodisiac are most frequent. There is scientific evidence that supports the use of these species in medicine, both at the extract level and at the active compound level, with in vivo tests in Plants 2021, 10, 2717 16 of 20 rats and mice, but there are no drugs derived from the species yet. The activity reported most frequently for Tragia extracts is antimicrobial and cancer-related, which suggests further research in those areas. Less than 20% of the Tragia species are considered medicinal. This implies vast potential for screening and discovery of active compounds. Most ethnopharmacological reports come from Asia and Africa, mainly East Africa and the Indian subcontinent. New world Tragia species have not been sufficiently studied and may prove to be a rich source of extracts and phytochemicals for drug research. Future directions for research include nanoparticles, the research into peptides extracted from Tragia species and the validation of medicines containing Tragia extracts against SARS-CoV-2. Author Contributions: Conceptualization, J.C.R.-B. and R.D.-C.; investigation, R.D.-C.; resources, J.C.R.-B.; writing, R.D.-C.; review and editing, J.C.R.-B. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Acknowledgments: We are grateful to Natalia Bailón-Moscoso for her many valuable suggestions that improved this work. We are also grateful to the Universidad Técnica Particular de Loja (UTPL) for supporting this research and open access publication. 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